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High expression of an intragenic long noncoding RNA misinterpreted as high FTO oncogene expression in NPM1 mutant acute myeloid leukemia

Leukemia volume 37, pages 901–904 (2023)Cite this article

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Further genetic analyses showed that of IFEX9-expressing AML cases 53%, 33 and 28% contained an FLT3-ITD, TET2, or IDH2 mutation, respectively. Of all IFEX9-positive cases, 33% were triple positive having an NPM1 mutation and FLT3-ITD with either a concurrent IDH2 or TET2 mutation (Fig. 2A, B).

Conversely, of all 96 NPM1 mutant AML cases, 31 (32%) expressed IFEX9. The presence of IFEX9 was confirmed in AML cases from TCGA [10] (Supplementary Fig. 1) and BLUEPRINT [9] (data not shown), where 21% (8/38) and 22% (2/9) of NPM1 mutated cases showed IFEX9 expression. IFEX9 was virtually absent in cytogenetically abnormal cases and healthy bone marrow samples from Beat AML (Fig. 2A) and sorted healthy blood cell types from BLUEPRINT (data not shown), indicating that this lncRNA is expressed in a leukemia subtype-specific manner.

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Fig. 1: High expression of an intragenic long noncoding transcript misinterpreted as high FTO gene expression in a large subset of NPM1 mutant AML.
Fig. 2: IFEX9 expression defines a transcriptomically defined immature subgroup of NPM1 mutant AML.

Data availability

For the original data, please contact Bert.vanderReijden@radboudumc.nl.

References

  1. Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, et al. FTO plays an oncogenic role in acute myeloid leukemia as a N(6)-methyladenosine RNA demethylase. Cancer Cell. 2017;31:127–41.

    Article  PubMed  Google Scholar 

  2. Lan N, Lu Y, Zhang Y, Pu S, Xi H, Nie X, et al. FTO—a common genetic basis for obesity and cancer. Front Genet. 2020;11:559138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, et al. Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia. Cancer Cell. 2019;35:677–91.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Qing Y, Su R, Chen J. Targeting FTO for cancer therapy and more. Aging. 2021;13:19080–2.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Xiao Q, Lei L, Ren J, Peng M, Jing Y, Jiang X, et al. Mutant NPM1-regulated FTO-mediated m(6)A demethylation promotes leukemic cell survival via PDGFRB/ERK signaling axis. Front Oncol. 2022;12:817584.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Qing Y, Su R, Chen J. RNA modifications in hematopoietic malignancies: a new research frontier. Blood. 2021;138:637–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Elkashef SM, Lin AP, Myers J, Sill H, Jiang D, Dahia PLM, et al. IDH mutation, competitive inhibition of FTO, and RNA methylation. Cancer Cell. 2017;31:619–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, et al. Functional genomic landscape of acute myeloid leukaemia. Nature 2018;562:526–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yi G, Wierenga ATJ, Petraglia F, Narang P, Janssen-Megens EM, Mandoli A, et al. Chromatin-based classification of genetically heterogeneous AMLs into two distinct subtypes with diverse stemness phenotypes. Cell Rep. 2019;26:1059–69.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.

    Article  PubMed  Google Scholar 

  11. Chen W, Rassidakis GZ, Medeiros LJ. Nucleophosmin gene mutations in acute myeloid leukemia. Arch Pathol Lab Med. 2006;130:1687–92.

    Article  CAS  PubMed  Google Scholar 

  12. Xie Z, Bailey A, Kuleshov MV, Clarke DJB, Evangelista JE, Jenkins SL, et al. Gene set knowledge discovery with enrichr. Curr Protoc. 2021;1:e90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374:422–33.

    Article  CAS  PubMed  Google Scholar 

  14. Heuser M, Freeman SD, Ossenkoppele GJ, Buccisano F, Hourigan CS, Ngai LL, et al. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2021;138:2753–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Marneth AE, Prange KHM, Al Hinai ASA, Bergevoet SM, Tesi N, Janssen-Megens EM, et al. C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation. Leukemia. 2018;32:828–36.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank KiKa (Dutch foundation Children Cancer Free) (project number 315) and the Dutch Cancer Society-funded COHERENT infrastructure (project number 13650) for support. RNA-seq data results published here are part from the Beat AML study group and partly based upon data generated by The Cancer Genome Atlas managed by the NCI and NHGRI. Information about TCGA can be found at http://cancergenome.nih.gov.

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  1. These authors contributed equally: Saioa Arza-Apalategi, Branco M. H. Heuts, Joost H. A. Martens, Bert A. van der Reijden.

Authors and Affiliations

  1. Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands

    Saioa Arza-Apalategi, Meike T. M. Dooijes, Daan Gilissen, Adrian J. P. van der Heijden, Joop H. Jansen & Bert A. van der Reijden

  2. Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA, Nijmegen, The Netherlands

    Branco M. H. Heuts & Joost H. A. Martens

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Contributions

SAA, BMHH, JHAM, and BAvdR designed and coordinated the research; SAA and MTMD performed the experiments; DG and SAA collected and analysed the data; AJPvdH arranged patient samples and informed consent; JHJ evaluated the results and SAA and BAvdR wrote the manuscript that was revised by all authors.

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Correspondence to Saioa Arza-Apalategi or Bert A. van der Reijden.

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The authors declare no competing interests.

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All patients signed the informed consent. The study was conducted in accordance with the Declaration of Helsinki and institutional guidelines and regulations from the Radboudumc Nijmegen (IRB number: CMO 2013/064).

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Arza-Apalategi, S., Heuts, B.M.H., Dooijes, M.T.M. et al. High expression of an intragenic long noncoding RNA misinterpreted as high FTO oncogene expression in NPM1 mutant acute myeloid leukemia. Leukemia 37, 901–904 (2023). https://doi.org/10.1038/s41375-023-01844-w

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